AVB-500 Plus Cabozantinib Shows Early Tolerability in Clear Cell RCC

Gail McIntyre, PhD

The combination of the GAS6/AXL inhibitor AVB-500 and cabozantinib (Cabometyx) has demonstrated acceptable tolerability when used in the treatment of patients with clear cell renal cell carcinoma (RCC), according to data from the phase 1b portion of a phase 1b/2 study (NCT04300140).¹

A total of 3 patients received the combination, with AVB-500 given at a dose of 15 mg/kg, the agent was found to be well tolerated with no unexpected signals observed. Based on the pharmacokinetics, pharmacodynamics, and safety data observed with the agent at this dose, along with approval issued by the Data and Safety Monitoring Board, Aravive Inc. has announced plans to expand the dosing of AVB-500 at 15 mg/kg to 3 more patients. By doing this, the goal is to identify the potential of launching the phase 2 portion of the research.

The clinical-stage biotechnology company also plans to continue to evaluate higher doses of AVB-500 in the phase 1b portion of the study to collect more data on the safety, pharmacokinetics, and pharmacodynamics of the regimen.

“We are pleased to announce the favorable results in the first cohort of our clear cell RCC phase 1b study, as we continue to advance AVB-500 and evaluate its ability to address an urgent, high unmet medical need in patients with advanced kidney cancer who have very low survival rates,” Gail McIntyre, PhD, chief executive officer of Aravive Inc., stated in a press release. “We continue to focus on difficult-to-treat, life-threatening cancers with AVB-500, and in addition to our clear cell RCC clinical trial, our lead indication in paclitaxel-resistant ovarian cancer is in a phase 3 clinical trial, and we recently announced that we plan to initiate a phase 1b/2 clinical trial in first-line metastatic pancreatic cancer in the second half of this year.”

AVB-500 is a novel, high-affinity, AXL decoy protein that adheres to GAS6 and hinders GAS6/AXL signaling. The decoy receptor was developed to have very high affinity for GAS6 by using a protein engineering approach; this resulted in a 200-fold greater affinity than native AXL. AVB-500 has also been shown to have an acceptable tolerability profile when evaluated in a study evaluating its use in normal healthy volunteers.^2,3

The phase 1b portion of the phase 1b/2 trial began in March 2021. This portion of the trial is anticipated to enroll up to 18 patients in the following 3 dosing arms: 15 mg/kg, 20 mg/kg, and 25 mg/kg. The objectives are to assess tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of the agent when paired with cabozantinib.

In the phase 2 portion, investigators expect to enroll 45 patients with advanced clear cell RCC who have progressed on first-line treatment and examine the recommended dose of AVB-500 identified in the phase 1b portion of the trial to combine with cabozantinib vs cabozantinib alone.

The primary end point of the trial is progression-free survival (PFS).

Previously, AVB-500 has also been investigated in combination with paclitaxel in patients with platinum-resistant ovarian cancer as part of a phase 1b study (NCT03639246).⁴ To be eligible for enrollment, patients needed to have high-grade serous ovarian cancer (HGSOC), endometrioid cancer, or undifferentiated adenocarcinoma that was platinum resistant. Patients also needed to have previously received 1 to 3 lines of therapy and have an ECOG performance status of 0 to 1.

A total of 53 patients were enrolled to the study. Of these, patients 23 received paclitaxel plus AVB-500 at 1 of the following 3 doses: 10 mg/kg (n = 16), 15 mg/kg (n = 3), or 20 mg/kg (n = 4); 30 patients were given pegylated liposomal doxorubicin (PLD) plus AVB-500 at the same doses: 10 mg/kg (n = 24), 15 mg/kg (n = 3), or 20 mg/kg (n = 3).

The mean age of study participants was 64 years, 96% were White, and 83% had HGSOC. In the paclitaxel cohort, 56% of patients (n = 13) had previously received treatment with bevacizumab vs 40% (n = 12) in the PLD cohort. Notably, patients in the paclitaxel cohort had more prognostic factors.

Among 19 patients, the doublet elicited an objective response rate (ORR) of 36.8%. Moreover, the 10 patients who had AVB-500 trough levels above the minimal efficacious concentration (MEC) experienced a higher ORR with the combination regimen, at 50.0%. Notably, the 9 patients who had not previously been exposed to bevacizumab (Avastin) were found to derive the highest ORR of the groups with the doublet, at 66.7%.

In the paclitaxel cohort, the overall clinical benefit rate (CBR) was 68.4%; in those who received the 10-mg/kg or the 15-mg/kg doses, the CBRs were 62.5% and 100%, respectively. The overall CBR in the PLD cohort was 60.0%; in the groups of patients who received the 10-mg/kg or the 15-mg/kg doses, the CBRs were 56.5% and 100%, respectively.

Moreover, the median PFS across doses in the paclitaxel and PLD cohorts were both 3.6 months (95% CI, 1.8-7.3; 95% CI, 1.8-5.0). In the paclitaxel subset, the median PFS in those who received the 10-mg/kg or the 15-mg/kg doses was 3.0 months (95% CI, 1.8-7.3) and 6.5 months (95% CI, 3.6–not determined [ND]), respectively. Within the PLD subset, the median PFS in those given the 10-mg/kg or the 15-mg/kg doses was 3.6 months (95% CI, 1.7-5.0) and 3.8 months (95% CI, ND–ND), respectively.

The median overall survival (OS) observed with the doublet in patients within the paclitaxel and PLD cohorts across doses was 14.1 months (95% CI, 8.1-19.3) and 12.6 months (95% CI, 9.1-14.2), respectively. In the paclitaxel subset, those who received 10-mg/kg dose experienced a median OS of 10.3 months (95% CI, 6.7-19.3) and it was not reached in those given the 15-mg/kg dose. In the PLD subset, the median OS at the 10- and 15-mg/kg doses was 12.7 months (95% CI, 10.2-15.6) and 7.6 months (95% CI, 6.0-9.1), respectively.

Most patients in both cohorts of the trial reported at least 1 treatment-emergent adverse effect. The toxicities most frequently experienced in the paclitaxel cohort included fatigue (26.1%), infusion-related reaction (21.7%), anemia (21.7%), and nausea (13%).

A phase 3 trial (NCT04729608) is now examining AVB-500 in combination with paclitaxel vs paclitaxel alone in patients with platinum-resistant ovarian cancer.⁵

References

1. Aravive announces positive initial results from phase 1b portion of the phase 1b/2 study of AVB-500 in combination with cabozantinib in clear cell renal carcinoma. News release. Aravive Inc. June 24, 2021. Accessed June 30, 2021. https://bit.ly/3qzQLsm
2. Kariolis MS, Miao YR, Jones DS, et al. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat Chem Biol. 2014;10(11):977-983. doi:10.1038/nchembio.1636
3. Kariolis MS, Miao YR, Diep A, et al. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J Clin Invest. 2017;127(1):183-198. doi:10.1172/JCI85610
4. Fuh K, Bookman M, Coleman R, et al. Phase I study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum resistant ovarian carcinoma. Presented at: Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021. Accessed June 30, 2021.
5. Study of AVB-S6-500 in combination with paclitaxel vs paclitaxel in patients with platinum-resistant ovarian cancer. ClinicalTrials.gov. Updated June 24, 2021. Accessed June 30, 2021. https://clinicaltrials.gov/ct2/show/NCT04729608